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The development and application of continuous flow chemistry methods for synthesis is a rapidly growing area of research. In particular, natural products provide demanding challenges to this developing technology. This review highlights successes in the area with an emphasis on new opportunities and technological advances.
A new
enabling technology for the pumping of organometallic reagents
such as n-butyllithium, Grignard reagents, and DIBAL-H
is reported, which utilises a newly developed, chemically resistant,
peristaltic pumping system. Several representative examples of its
use in common transformations using these reagents, including metal–halogen
exchange, addition, addition–elimination, conjugate addition,
and partial reduction, are reported along with examples of telescoping
of the anionic reaction products. This platform allows for truly continuous
pumping of these highly reactive substances (and examples are demonstrated
over periods of several hours) to generate multigram quantities of
products. This work culminates in an approach to the telescoped synthesis
of (E/Z)-tamoxifen using continuous-flow organometallic
reagent-mediated transformations.
The development of a tube-in-tube reactor based on a semipermeable polymer membrane has enabled the efficient transfer of gases into liquid flow streams. In this work we describe the scalability and throughput of this reactor when applied to ammonia gas. This is made possible by a convenient titration method to rapidly assess a wide range of parameters including the liquid and gas configuration, reactor temperatures, flow rates, and solvent polarity. These data are then employed in a scaling-up process affording alkyl thioureas and are ultimately applied to a telescoped procedure leading to the antiinflammatory agent fanetizole on a multigram scale.
The present work describes the preparation of three novel series of compounds based on the structure of goniothalamin, a natural styryl lactone which has been found to display cytotoxic and antiproliferative activities against a variety of cancer cell lines. A focused library of 29 novel goniothalamin analogues was prepared and evaluated against seven human cancer cell lines. While the γ-pyrones and the aza-goniothalamin analogues were less potent than the lead compound, 2,4-dimethoxy analogue 88 has shown to be more potent in vitro than goniothalamin against all cancer cell lines evaluated. Furthermore, it was more potent than doxorubicin against NCI-ADR/RES, OVCAR-03 and HT-29 while being less toxic to human keratinocytes (HaCat). The 3,5-dimethoxy analogue 90 and 2,4,5-trimethoxy analogue 92 also displayed promising antiproliferative activity when compared to goniothalamin (1). These results provide new elements for the design and synthesis of novel representatives of this family of natural compounds.
The
dehydration reaction of d-(−)-fructose into
5-(hydroxymethyl)furfural (HMF) in both batch and continuous flow
conditions was comprehensively studied using the statistical tool
design of experiments (DoE), employing i-PrOH/DMSO
as the solvent system in the presence of the solid acid catalyst Amberlyst-15.
Initially, screening of different alcohols (MeOH, EtOH, i-PrOH, and t-BuOH) showed that i-PrOH provides better selectivity and yield compared to the other
alcohols, along with minimum formation of byproducts when associated
with small amounts of DMSO (15% v/v) as a cosolvent. To confirm the
selectivity of the reaction, all of the possible byproducts (HMF-ethers
and/or ketals) formed during the reaction between HMF and i-PrOH were synthesized. Factors like temperature, amount
of DMSO, time (flow rate), and catalyst loading were evaluated by
a full factorial design, and the results indicated that temperature
presents the greatest influence in both batch (HMF in 71% yield) and
continuous flow regime (HMF in 95% yield). In addition, a FTIR device
was coupled to the continuous flow micro reactor, allowing for the
first time constant in-line monitoring for this transformation, thereby
showing the long-term stability of Amberlyst-15 and process robustness.
We present a comprehensive review of the advent and impact of continuous flow chemistry with regard to the synthesis of natural products and drugs, important pharmaceutical products and definitely responsible for a revolution in modern healthcare. We detail the beginnings of modern drugs and the large scale batch mode of production, both chemical and microbiological. The introduction of modern continuous flow chemistry is then presented, both as a technological tool for enabling organic chemistry, and as a fundamental research endeavor. This part details the syntheses of bioactive natural products and commercial drugs.
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